A systematic review of microsurgical reconstruction of the jaws using vascularized fibula flap technique in patients with bisphosphonate-related osteonecrosis.

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INTRODUCTION

Bisphosphonates are a new class of agents that have been increasingly recommended for use in patients with osteoporosis, Paget's disease of bone, hypercalcemia of malignancy, osteolytic bone metastases, and osteolytic lesions of multiple myeloma ( Figure 1 ) 7 , 19 . Despite the benefits related to use of these medications, osteonecrosis of the jaws is a significant complication in a subset of patients receiving these drugs in particular with intravenous administration. Based on a growing number of case reports and institutional reviews, bisphosphonate therapy may cause exposed and necrotic bone that is isolated to the jaw 33 , 35 . This complication could present after simple dentoalveolar surgery. The phenomenon of bisphosphonate-related osteonecrosis of jaws (BRONJ) was recognized a few years after their approval for use 1 . Reports first appeared in 2003, alerting the dental and medical communities of this complication 28 , 37 , 38 , 43 . Since brought to light in 2003 23 , 47 , well over 400 reports have been published concerning BRONJ. Despite this large volume of work, there are few data yet many hypotheses concerning the underlying pathophysiology. The physiologic effects of bisphosphonates on bone cells, osteoblasts, osteoclasts, and osteocytes, have recently been comprehensively reviewed 39 , 40 , 41 .

Osteoclasts represent the main cellular target of bisphosphonates 46 . Specifically, bisphosphonates repress osteoclast-mediated bone remodeling, through disruption of intracellular pathways. As remodeling is a vital role process in tissue renewal and bone healing, bisphosphonate-induced remodeling suppression causes relevant effects on various tissue-level properties 5 , 7 , 27 , 42 .

The effects of bisphosphonates on osteocytes are less clear and more controversial. There is a high awareness on both direct and indirect effects, most of which are centered around the viability and integrity of these cells and their environment 3 , 31 , 32 .

Although systemic bone formation is reduced in the presence of bisphosphonates, this is primarily an indirect consequence of remodeling suppression and the coupling between resorption and formation. At the level of the individual basic multicellular unit, osteoblast activity appears unaffected 9 , 13 . Reports from small animal models suggest that bisphosphonates may suppress osteoblastic bone formation directly on those surfaces undergoing bone formation without prior resorption (i.e., formation modeling) 21 , although large animal models do not show a similar suppressive effect on periosteal surfaces 4 , 26 .

In addition, this evidence shows that osteoclasts and/or osteocytes are the main cells of interest for BRONJ pathogenesis. The basic premise of this hypothesis is that the jaw has a high remodeling rate and bisphosphonates suppress remodeling. There is no debate about the latter because this is the principal mechanism of action of bisphosphonates 34 , 40 , 41 . It is also clear that remodeling, specifically within the intracortical envelope, is considerably higher in the jaw compared with other skeletal sites. The BRONJ hypothesis thus follows the idea that because remodeling is high in the jaw, and bisphosphonates suppress remodeling, this likely plays a role in the pathophysiology of BRONJ 3 , 24 .

Current information on the prevalence and incidence of BRONJ (and much rarer non-bisphosphonate-associated events) is poor. These data are hampered by inconsistent definitions, as well as incomplete reporting. Unfortunately, with current information sources, it is not possible to determine the prevalence or incidence rates 16 .

Strategies for the treatment of patients with, or at risk of, BRONJ were defined in the American Association of Oral and Maxillofacial Surgeons (AAOMS) Position Paper on Bisphosphonate-Related Osteonecrosis of the Jaws (Position Paper) and approved by the Board of Trustees in September 2006 1 . The Position Paper was developed by a task force appointed by the Board and composed of clinicians with extensive experience in treating these patients and basic science researchers. The knowledge base and experience in addressing BRONJ has expanded, necessitating modifications and refinements to the original Position Paper. The task force was then called together again in August 2008 to review the 2006 recommendations, appraise the current published data, and revise the Position Paper and recommendations, where indicated. This update contains revisions to the diagnosis and staging and management strategies and highlights the status of basic science research 35 , 36 , 38 . The purpose of this updated Position Paper is to provide ( Figure 2 ): 1. Perspectives on the risk of developing BRONJ and the risks and benefits of bisphosphonates to facilitate medical decision-making of both the treating physician and the patient; 2. Guidance to clinicians regarding the differential diagnosis of BRONJ in patients with a history of treatment with intravenous (IV) or oral bisphosphonates; 3. Guidance to clinicians on possible BRONJ prevention measures and treatment of patients with BRONJ according to the presenting stage of the disease.

The aim of this systematic review was to assess the role of the microsurgical reconstruction of the jaws in patents affected by bisphosphonate-related osteonecrosis ( Figure 3 ), highlighting the clinical effectiveness at short- and long-term using the vascularized fibula free flap, and evaluating biological complications after an observation period of at least 12 months in the cases of BRONJ at the 3 rd stage (as per Position Paper of American Association of Oral and Maxillofacial Surgeons -AAOMS).

MATERIAL AND METHODS

Search strategy and inclusion criteria

A systematic review of the English literature was conducted for selected articles published from January 1976 to June 2009.

Searching was performed using an full-text electronic journal database (PubMed). The following key word combinations were applied: jaw osteonecrosis, osteonecrosis bisphosphonate, bisphosphonate-related osteonecrosis, microsurgical reconstruction of the jaws, vascularized fibula flap. Manual searches of the bibliographies of all full-text articles and related reviews, selected from the electronic search, were also performed. Furthermore, manual searching was conducted in the following journals for the considered period: American Journal Medicine, Bone, British Journal of Oral and Maxillofacial Surgery, Clinical Oral Implants Related Research, Journal of Periodontology, Journal of Oral and Maxillofacial Surgery, Journal of Oral Pathology and Medicine, Journal of Prosthetic Dentistry, Oral Disease, Oral Oncology, Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics, Quintessence International and The Laryngoscope.

From this extensive search, it was obvious that there were no randomized controlled clinical trials (RCTs) available, prospective or retrospective studies. In the absence of RCTs, prospective or retrospective studies, this systematic review was based on clinical cases (case series, case report):

- that had a mean follow-up time of 12 months or more;

- obtained from publications within English dental literature;

- where patients included had been examined clinically at follow-up visits.

Selection of studies

Titles and abstracts of the searches were initially screened by two independent reviewers for possible inclusion in the review. The full text of all relevant studies was then obtained for independent assessment by the reviewers. Any disagreement was resolved by discussion. Figure 4 describes the identification process of the 5 studies which were selected from an initial yield of 947 titles. Data were extracted using a data extraction form. Disagreement regarding data extraction was resolved by consensus, after discussions ( Figure 1 ).

Excluded studies

Six out of 11 full-text articles examined were excluded from the final analysis for different reasons: the mean observation period was <12 months, the type of reconstructions was not performed with vascularized fibula flap and/or the osteonecrosis was an osteoradionecrosis.

Data extraction

Information on the surgical reconstructions and on biological complications was retrieved from the 5 included studies. Biological complications during the surgery, after the surgery and in the follow-up period were highlighted.

RESULTS

A total of 22 patients were observed and treated in 5 different studies where 13 patients received a vascularized osteocutaneous fibula free flap reconstruction (59.09%) and 9 received only a vascularized fibula free flap reconstruction (40.90%) ( Figures 5 and 6 ). All flaps survived completely and the postoperative course was uneventful with cumulative survival rate (CSR) of 100% ( Figure 6 ). Exceptions were represented by 6 cases (27.27%): four patients (18.18%) had postoperative wound complications. The most common complication was fistula which in one case required a pectoralis myogenous flap for wound closure; in another case (4.54%), the rupture of a miniplate was observed but it did not require any surgical exploration in a third case (4.54%), a small hematoma formed in the anterior portion of the neck incision after approximately 2 weeks from the operation ( Figure 7 ). Two patients died of cancer-related disease 8 weeks and 16 month after surgery, with no signs of recurrent BRONJ. BRONJ-related facial pain and halitosis stopped completely after the operation in all patients. The donor leg healed without complications in all cases. Stable oral lining and solid bone union were achieved in all patients. In all studies no complications were reported to the vascularized fibula free flap with 100% of success rate and recurrence of the osteonecrosis were noted only in two cases (9.09%) ( Figure 7 ).

DISCUSSION

BRONJ is a challenging complication to treat, in terms of both disease control and quality of life 2 , 46 , and its treatment is still under discussion and unclear. Although recommendations for the management of this disease exist, they are dependent on a small group of patients. In addition, accordance about prevention or conservative treatment as the basis for "at risk" patients exist 18 , 23 , 25 . Medical treatments are routinely employed together with conservative surgery of the exposed necrotic bone 22 . However, the initial treatment should include improvement of oral hygiene and systemic antibiotics to prevent secondary infection and pain 8 , 14 .

For the management of exposed necrotic bone, additional surgical debridement or sequestrectomy with primary mucosal closure seems to be effective in most cases. If there are recurrences at the conservative treatment, bone segment should be considered as it seems to be more successful than wound debridement alone 29 .

The reconstruction of subtotal mandibulectomy defects requires vascularized bone to promote healing and provide adequate soft-tissue support and oral competence 11 , 45 . Engroff and Kim 12 (2007), reported two cases of microvascular reconstruction of the mandible in BRONJ patients. Two lateral mandibular defects were successfully reconstructed with a fibula flap 12 .

Nocini, et al. 30 (2009) in their case series have recently shown that a properly planned surgical resection has high curative potential in BRONJ patients. Mucke, et al. 29 (2009) have shown that the effect of the transferred flap with also the vascularized iliac crest might represent a valuable technique. Despite the co-morbid conditions, the free bone-flap survival, the overall morbidity and the hospital stay, patients treated for osteonecrosis were comparable to that of patients whose mandibles are reconstructed because of osteoradionecrosis 10 , 17 .

Patients with reasonable life expectancy with regard to their malignant disease should be considered for microvascular tissue transfer after aggressive resection of the affected region. The quality of life can be increased and a subset of patients with advanced disease can be cured of BRONJ. As already mentioned, the basic pathogenesis of this disease seems to be an avascular osteonecrosis, particularly involving the jaws. It seems therefore to be possible to treat patients with microvascular reconstruction of the jaws as the transferred bone receives direct blood supplementation from the anastomosed artery (superior thyroid or facial artery). The effect of the transferred flap with a new input of blood supply might be one of the reasons for the uneventful postoperative course in all patients. However, the cutaneous component of the flap provides additional soft tissue for reconstruction of resected fistulas and helps establish tension free wounds in the oral cavity. Seth, et al. 44 (2010) have shown recently that vascularized bone graft reconstruction with osteocutaneous fibula free flap is feasible, offers a high success rate with only few postoperative wound complications selected patients with advanced cases of BRONJ.

According to literature 12 , 15 , 29 , 30 , 44 , radical surgical treatment has to be considered when:

- BRONJ seems to involve a large area of the jaws;

- the disease is not resolved by conservative therapy;

- the donor site of the patient is well perfused;

- the donor site of the patient is excluded by bone metastases.

However, the possibility of transferring cancer cells to the oral cavity during jawbone reconstruction with free bone flaps in patients with disseminated cancer or multiple myeloma has not been observed. Furthermore, fibula is rarely the site of metastatic bone disease or multiple myeloma 20 . Mandibular reconstruction using bone-containing microvascular flaps such as a fibula free flap is possible after a large resection and it gives also the opportunity of oral prosthetic rehabilitation using dental implants, as described by Ferrari, et al. 15 (2008) in their clinical report.

CONCLUSIONS

Osteonecrosis is a rare but significant complication of bisphosphonate therapy, and current literature supports only conservative defect reconstruction. These measures may not provide optimum reconstruction to achieve a well-vascularized healing environment, adequate oral function, and facial cosmetics. Microsurgical reconstruction of the jaws plays a critical role in improving the patient's quality of life. After an observation period of 12 months from microsurgical reconstruction of the jaws, high survival rates can be expected with few recurrences of osteonecrosis (9.09%). This, in turn, means that vascularized fibula flap technique has been well accepted by the clinician findings. Despite the limited number of patients found in the review of literature, this kind of treatment appears to be practicable in BRONJ-resected patients and does not seem to influence the natural course of the primary disease.

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